Journal article
Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities
JCI Insight, Vol.1(4), e86183
2016
DOI: 10.1172/jci.insight.86183
PMCID: PMC4855508
PMID: 27158673
Abstract
BACKGROUND. Airflow obstruction is common in cystic fibrosis (CF), yet the underlying pathogenesis remains incompletely understood. People with CF often exhibit airway hyperresponsiveness, CF transmembrane conductance regulator (CFTR) is present in airway smooth muscle (ASM), and ASM from newborn CF pigs has increased contractile tone, suggesting that loss of CFTR causes a primary defect in ASM function. We hypothesized that restoring CFTR activity would decrease smooth muscle tone in people with CF. METHODS. To increase or potentiate CFTR function, we administered ivacaftor to 12 adults with CF with the G551D-CFTR mutation; ivacaftor stimulates G551D-CFTR function. We studied people before and immediately after initiation of ivacaftor (48 hours) to minimize secondary consequences of CFTR restoration. We tested smooth muscle function by investigating spirometry, airway distensibility, and vascular tone. RESULTS. Ivacaftor rapidly restored CFTR function, indicated by reduced sweat chloride concentration. Airflow obstruction and air trapping also improved. Airway distensibility increased in airways less than 4.5 mm but not in larger-sized airways. To assess smooth muscle function in a tissue outside the lung, we measured vascular pulse wave velocity (PWV) and augmentation index, which both decreased following CFTR potentiation. Finally, change in distensibility of <4.5-mm airways correlated with changes in PWV. CONCLUSIONS. Acute CFTR potentiation provided a unique opportunity to investigate CFTR-dependent mechanisms of CF pathogenesis. The rapid effects of ivacaftor on airway distensibility and vascular tone suggest that CFTR dysfunction may directly cause increased smooth muscle tone in people with CF and that ivacaftor may relax smooth muscle. FUNDING. This work was funded in part from an unrestricted grant from the Vertex Investigator-Initiated Studies Program. Acute potentiation of cystic fibrosis transmembrane conductance regulator (CFTR) function in people with cystic fibrosis and a G551D-CFTR mutation reveals that CFTR dysfunction may directly increase smooth muscle tone.
Details
- Title: Subtitle
- Acute administration of ivacaftor to people with cystic fibrosis and a G551D-CFTR mutation reveals smooth muscle abnormalities
- Creators
- Ryan J Adam - University of Iowa, Roy J. Carver Department of Biomedical EngineeringKatherine B Hisert - University of WashingtonJonathan D Dodd - University College DublinBrenda Grogan - University College DublinJanice L Launspach - University of IowaJanel K Barnes - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USACharles G Gallagher - University College DublinJered P Sieren - University of IowaThomas J Gross - University of Iowa, Internal MedicineAnthony J Fischer - Pappajohn Biomedical Institute, University of Iowa, Iowa City, Iowa, USAJoseph E Cavanaugh - University of Iowa, BiostatisticsEric A Hoffman - University of Iowa, Roy J. Carver Department of Biomedical EngineeringPradeep K Singh - University of WashingtonMichael J Welsh - University of Iowa, Internal MedicineEdward F McKone - University College DublinDavid A Stoltz - University of Iowa, Roy J. Carver Department of Biomedical Engineering
- Resource Type
- Journal article
- Publication Details
- JCI Insight, Vol.1(4), e86183
- DOI
- 10.1172/jci.insight.86183
- PMID
- 27158673
- PMCID
- PMC4855508
- NLM abbreviation
- JCI Insight
- ISSN
- 2379-3708
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical Investigation
- Language
- English
- Date published
- 2016
- Academic Unit
- Statistics and Actuarial Science; Roy J. Carver Department of Biomedical Engineering; Neurology; Radiology; Molecular Physiology and Biophysics; Pulmonary Medicine; Stead Family Department of Pediatrics; Biostatistics; Injury Prevention Research Center; Neurosurgery; Internal Medicine
- Record Identifier
- 9983985891002771
Metrics
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